Microbial infections give rise to various diseases depending on the site of infection and the nature of the microorganism. In some cases, infection can lead to death, especially in the young, the elderly and in immuno-compromised individuals. Bacterial infections are primarily treated with antibiotics. However, the incidence of infections caused by antibiotic resistant microorganisms is on the increase. Antibiotic-resistant microorganisms cannot readily be treated with conventional antibiotics. Among the microorganisms known to have developed resistance to certain antibiotics are bacterial strains such as Streptococcus pneumoniae. The severity of such infections often requires immediate medical intervention and the treatment of patients by intravenous administration of antibiotics.
Cethromycin, also known as ABT-773, is a ketolide antibiotic that has shown promise in the treatment of microbial infections, for instance respiratory tract infections caused by macrolide-resistant microorganisms. While cethromycin may be used in the treatment of macrolide-resistant infections, it has certain drawbacks. Cethromycin exhibits strong inhibition of cytochrome P4503A4 (CYP3A4), an important metabolic enzyme involved in the oxidation of xenobiotics in vivo. As a result of its strong CYP3A4 inhibition, cethromycin displays drug-drug interaction which causes problems during concomitant administration with other drugs metabolized by cytochrome P450 enzymes, i.e., CYP3A4. It has been estimated that CYP3A4 metabolizes about half of all drugs on the market and so the incompatibility associated with co-administration of cethromycin with other drugs is a problem. In vitro experiments with human liver microsomes and recombinant CYP isoforms indicate that cethromycin is metabolized to one primary metabolite (M-1) and two secondary metabolites. The M-1 metabolite is formed by CYP3A (both CYP3A4 and CYP3A5 are able to metabolize cethromycin). Further in vitro work demonstrated that cethromycin was able to inhibit CYP3A-dependent nifedipine oxidation with an IC50 of 0.63 μM (482.5 ng/mL). (see Katz et al, Clin Pharmacol Ther. 75:516-28, (2004); and Cethromycin for the Treatment of Community-Acquired Bacterial Pneumonia, FDA Briefing Document for Anti-Infective Drugs Advisory Committee Meeting, Jun. 2, 2009, wayback.archive-it.org/7993/20170405205229/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM161847.pdf)
Solithromycin is a ketolide antibiotic undergoing clinical development for the treatment of community-acquired pneumonia and other infections. Solithromycin exhibits excellent in vitro activity against a broad spectrum of Gram-positive respiratory tract pathogens, including macrolide-resistant strains. Solithromycin is both a CYP3A4 and P-gp substrate, and is also a strong inhibitor of CYP3A4 and a moderate inhibitor of P-gp. The drug-drug interaction profile of solithromycin is consistent with that of previously approved macrolides. Solithromycin should not be administered to patients who are receiving strong or moderate CYP3A/P-gp inducers because of the risk of subtherapeutic exposure and loss of efficacy. Concomitant administration of solithromycin with sensitive CYP3A and/or P-gp substrates that have potential adverse effects due to increased plasma concentrations (e.g. digoxin) may require monitoring and/or dose adjustment of the concomitantly administered drug. The profile for potential drug-drug interactions is consistent with that of other macrolides. (see Solithromycin For The Treatment Of Community Acquired Bacterial Pneumonia, Briefing Document For The Antimicrobial Drugs, Advisory Committee Meeting Date: Nov. 4, 2016, www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM527691.pdf).
There is a need for new drugs that display adequate antimicrobial properties similar to cethromycin against susceptible and/or resistant strains such as S. Pneumonia, but have limited ability to inhibit CYP3A4 in order to improve the safety of drug co-administration.